title: Kappa opioid receptor activation blocks progressive neurodegeneration after kainic acid injection.
abstract: We recently demonstrated that endogenous prodynorphin-derived peptides mediate anticonvulsant, antiepileptogenic and neuroprotective effects via kappa opioid receptors (KOP). Here we show acute and delayed neurodegeneration and its pharmacology after local kainic acid injection in prodynorphin knockout and wild-type mice and neuroprotective effect(s) of KOP activation in wild-type mice. Prodynorphin knockout and wild-type mice were injected with kainic acid (3 nmoles in 50 nl saline) into the stratum radiatum of CA1 of the right dorsal hippocampus. Knockout mice displayed significantly more neurodegeneration of pyramidal cells and interneurons than wild-type mice 2 days after treatment. This phenotype could be mimicked in wild-type animals by treatment with the KOP antagonist GNTI and rescued in knockout animals by the KOP agonist U-50488. Minor differences in neurodegeneration remained 3 weeks after treatment, mostly because of higher progressive neurodegeneration in wild-type mice compared with prodynorphin-deficient animals. In wild-type mice progressive neurodegeneration, but not acute neuronal loss, could be mostly blocked by U-50488 treatment. Our data suggest that endogenous prodynorphin-derived peptides sufficiently activate KOP receptors during acute seizures, and importantly in situations of reduced dynorphinergic signaling-like in epilepsy-the exogenous activation of KOP receptors might also have strong neuroprotective effects during excitotoxic events.
authors.affiliation: Department of Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Schunk
authors.forename: Cornelia
authors.initials: C
authors.lastname: Aigner
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Gregor
authors.initials: G
authors.lastname: Wenning
authors.forename: Herbert
authors.initials: H
authors.lastname: Herzog
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarzer
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009019:Morphinans / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D004745:Enkephalins; D006146:Guanidines; D009019:Morphinans; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; C033660:preproenkephalin; D007608:Kainic Acid